The abnormality in a gastrointestinal motor function by various causes such as chronic gastritis, gastrectomy, peptic ulcer, diabetes mellitus or scleroderma results in the reflux of gastric contents into the esophagus, delayed emptying of the contents and the depression of small and large intestinal functions.
This can lead to several gastrointestinal disorders including nausea, vomiting, heartburn, anorexia, abdominal distension, epigastric dysphoria, abdominaglia, constipation and further reflux esophagitis. One cause of the diseases such as irritable bowel syndrome and spurious ileus is considered to be the depression in gastrointestinal motility.
The agents for the treatment of these conditions and diseases include direct cholinergic agent (e.g. Aclatonium Napadisilate) or Dopamine antagonist (e.g. Domperidone).
However, it is known that these known agents have the problems of insufficent therapeutic effects and side effects including diarrhea and extrapyramidal syndrome.
The gastrointestinal motility is controlled by both sympathetic and parasympathetic nervous systems. In the parasympathetic nervous system, acetylcholine is one of the most important neurotransmitters participating in the control of gastrointestinal motility. The release of acetylcholine from the nerves in the nerve plexus of gastrointestinal tract may induce the contraction of gastrointestinal tract. Accordingly, the accelerated release of acetylcholine from the nerve plexus of gastrointestinal tract results in sthenia of gastrointestinal motility.
Recently, a 5-HT.sub.4 receptor was found in gastrointestinal tract. The 5-HT.sub.4 receptor was reported to control the release of acetylcholine in the gastrointestinal nerve Trends in Pharmacological Science, Vol. 13, 141-145, (1992)!. Thus, compounds acting on the 5-HT.sub.4 receptor in the gastrointestinal tract and promoting the release of acetylcholine may be a more effective gastrokinetic agent with less side effects.
On the other hand, WO 9303725 discloses that (1-butyl-4-piperidyl)methyl-1-methylindazole-3-carboxylate (Example 10) has a 5-HT.sub.4 receptor antagonist activity, and is of potential use in the treatment of diseases derived from 5-HT, diarrhea of irritable bowel syndrome due to the 5-HT activated intestinal nerve, cardiovascular disorders and CNS disorders. U.S. Pat. No. 3,145,215 discloses that N-2-(4-methyl-1-piperazinyl)ethyl!-1H-indazole-3-carboxamide has hypotensive activity. However, it is not reported that those compounds have 5-HT.sub.4 receptor agonist activities and gastrointestinal prokinetic actions.
Aliment. Pharmacol. Ther., Vol. 6, 273-289, 1992 suggests that irritable bowel syndrome exists as two types, constipation-type and diarrhea-type irritable bowel syndromes and 5-HT.sub.4 receptor agonists are useful in the treatment of constipation-type irritable bowel syndrome, while Medicinal Research Reviews, Vol. 13, 633-662, 1993 suggests that 5-HT.sub.4 receptor antagonists are useful in the treatment of diarrhea-type irritable bowel syndrome.
WO 9312785 discloses that 5-HT.sub.4 receptor antagonists and agonists are of potential use in the treatment of conditions associated with bladder hypersensitivity and a poorly functioning bladder.
By elucidation of new compounds having a 5-HT.sub.4 receptor agonist activity, it has been demanded to develop a medicine based on such a mechanism of action that acts on the 5-HT.sub.4 receptor controlling the release of acetylcholine in the gastrointestinal nerve to promote the release of acetylcholine from the nerves in the nerve plexus of gastrointestinal tract, resulting in sthenia of a gastrointestinal motion, i.e., a 5-HT.sub.4 receptor agonist.